title: Nonredundant roles of IL-10 and TGF-β in suppression of immune responses to hepatic AAV-factor IX gene transfer.
abstract: Hepatic gene transfer using adeno-associated viral (AAV) vectors has been shown to efficiently induce immunological tolerance to a variety of proteins. Regulatory T-cells (Treg) induced by this route suppress humoral and cellular immune responses against the transgene product. In this study, we examined the roles of immune suppressive cytokines interleukin-10 (IL-10) and transforming growth factor-β (TGF-β) in the development of tolerance to human coagulation factor IX (hF.IX). Interestingly, IL-10 deficient C57BL/6 mice receiving gene transfer remained tolerant to hF.IX and generated Treg that suppressed anti-hF.IX formation. Effects of TGF-β blockade were also minor in this strain. In contrast, in C3H/HeJ mice, a strain known to have stronger T-cell responses against hF.IX, IL-10 was specifically required for the suppression of CD8(+) T-cell infiltration of the liver. Furthermore, TGF-β was critical for tipping the balance toward an regulatory immune response. TGF-β was required for CD4(+)CD25(+)FoxP3(+) Treg induction, which was necessary for suppression of effector CD4(+) and CD8(+) T-cell responses as well as antibody formation. These results demonstrate the crucial, nonredundant roles of IL-10 and TGF-β in prevention of immune responses against AAV-F.IX-transduced hepatocytes.
authors.affiliation: Division of Cellular and Molecular Therapy, Department of Pediatrics, University of Florida, Gainesville, Florida 32610, USA. bhoffman@ufl.edu
authors.forename: Brad E
authors.initials: BE
authors.lastname: Hoffman
authors.forename: Ashley T
authors.initials: AT
authors.lastname: Martino
authors.forename: Brandon K
authors.initials: BK
authors.lastname: Sack
authors.forename: Ou
authors.initials: O
authors.lastname: Cao
authors.forename: Gongxian
authors.initials: G
authors.lastname: Liao
authors.forename: Cox
authors.initials: C
authors.lastname: Terhorst
authors.forename: Roland W
authors.initials: RW
authors.lastname: Herzog
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005164:Factor IX; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D005822:Genetic Vectors / Q000235:genetics*; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism*; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D007371:Interferon-gamma; D005164:Factor IX